WO2005023758A2 - Methode de preparation de losartan potassium de forme i - Google Patents

Methode de preparation de losartan potassium de forme i Download PDF

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Publication number
WO2005023758A2
WO2005023758A2 PCT/IB2004/002879 IB2004002879W WO2005023758A2 WO 2005023758 A2 WO2005023758 A2 WO 2005023758A2 IB 2004002879 W IB2004002879 W IB 2004002879W WO 2005023758 A2 WO2005023758 A2 WO 2005023758A2
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Prior art keywords
losartan
solvent
water
organic solvent
potassium
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PCT/IB2004/002879
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English (en)
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WO2005023758A3 (fr
Inventor
Bakulesh Mafatlal Khamar
Indravadan Ambalal Modl
Rao Madhusudana (Gajula)
Radha, (Achanatha)
Murali Rajappa
Original Assignee
Bakulesh Mafatlal Khamar
Indravadan Ambalal Modl
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Application filed by Bakulesh Mafatlal Khamar, Indravadan Ambalal Modl filed Critical Bakulesh Mafatlal Khamar
Priority to EP04769282A priority Critical patent/EP1663998A2/fr
Publication of WO2005023758A2 publication Critical patent/WO2005023758A2/fr
Publication of WO2005023758A3 publication Critical patent/WO2005023758A3/fr
Priority to US10/570,824 priority patent/US20070249839A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • This invention relates to a process for the preparation of losartan potassium and its polymorphic form I.
  • Losartan is generally prepared from 2-Rutyl-4-chloro-5- (hydroxymethyl)-l -[[2'- f(triphenylmethyl) tetrazol-5-yl] biphenyI-4-yl] methyl] imidazole, commonly referred as Trityl Losai tan (II).
  • Trityl Losai tan II
  • EP 253310 discloses a process, wherein 2-n-butyl-4-chloro-l H-imidazolyl-5- melhanol (III) is coupled with 5-(4'-bromomethyl-l , l '-biphenyl-2-yl)-2- lriphenylmethyl-2H-tetrazole (IV) in N, N-dimethylformamide as solvent in presence of sodium methoxide as the base to furnish trityl losartan.
  • the other bases that have been claimed are sodium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate and amine bases such as triethyl amine and pyridine.
  • the coupling reaction results in a mixture of trityl losartan and its regio isomer (V). These are separated by column chromatography.
  • US patents 5,130,439 and 5,310,928 disclose a method for coupling (IV) and (VI) in N,N- dimethylacetamide solvent in the presence of anhydrous potassium carbonate as base.
  • the imidazole aldehyde (VI) gives predominantly the desired regio isomer (VII).
  • the intermediate VII is then reduced with sodium borohydride to furnish the trityl losartan.
  • the product is isolated by extraction into toluene from aqueous N, N-dimethylacetamide, concentration of the toluene solution and crystallization using ethyl acetate or ethanol as solvent.
  • the synthesis steps are depicted as follows.
  • Losartan is prepared by coupling (III) and (IV) in N.N-dimethylformamide in the presence of sodium methoxide.
  • the desired compound is isolated after vacuum distillation of solvent followed by extractive work-up.
  • the resultant product mixture is purified by chromatography.
  • the trityl losartan thus formed is treated with 3.4N hydrochloric acid in methanol at about 10°C to give losartan.
  • the US Patents 5,138,069, 5,128,355 and 5,155,118 also disclose another process for making trityl losartan, where in the coupling between IV and VI is carried out in a biphasic solvent system comprising of chlorinated solvent and water.
  • the reaction is carried out at room temperature in presence of sodium hydroxide as the base and aliquat 336 as the phase transfer catalyst.
  • the resulting intermediate VII is then reduced in situ with sodium borohydride to furnish trityl losartan.
  • Patent No. 5,206,374, 5310928 and 5962500 disclose another process for preparing losartan in which 5-phenyltetrazole (X) is converted into the boronic acid coupling partner (XII) for the Suzuki reaction by tritylation of phenyltetrazole with trityl chloride in presence of a non- nucleophilic base, ortho metalation with n-butyl lithium, followed by reaction with triisopropylborate.
  • EP 470,794 and EP 470,795 describe a method for the manufacture of biphenyl carbonitriles (XVI). These patents also describe a method of preparation of trityl losartan by coupling of intermediates (III) and (IV) employing the procedure described in EP 253,310.
  • US patent 5,608,075 discloses the polymorphic forms of losartan, wherein the trityl losartan is deprolected with H 2 SO4 in 50:50 acetonitrile water and the free acid is treated with OH solution.
  • the aqueous solution containing losartan potassium is added slowly to a refluxing azeotropic mixture of cyclohexane/iso propanol and the ternary azeotrope cyclohexane/iso propanol/water is distilled till the water content of the pot is less than 0.05%.
  • the white crystalline solid thus obtained is polymorphic form-I, which is characterized by DSC, XRD and IR.
  • Polymorphic form- II is prepared by heating form-I in a DSC cell. This process is also described in US 5,859,258.
  • US patent 6,710,183 discloses the synthesis of losartan potassium starting from trityl losartan, wherein trityl losartan is reacted in an alcohol of formula R-OH (where R is O to C4 straight chain al yl group) with 0 1 to 1 equivalent KOH.
  • Losartan potassium thus formed is isolated after crystallizing out by changing the solvent to an aprotic or weakly protic solvent.
  • the alcohol used is preferably methanol and the protic dipolar solvent used for the crystallization of the final product is preferably acetonitrile or straight or branched chain or cyclic ajiphatic hydrocarbons.
  • EP 1294712 discloses the process to manufacture losartan potassium form-I, wherein trityl losartan or losartan is suspended in a solvent and KOH is added to obtain a clear solution, which is then concentrated undei leduced pressure to remove most of the solvent.
  • An anti solvent is added to crystallize losai la potassium.
  • the solvents to prepare losartan potassium include methanol, ethanol, and butanol but preferably the salt formation is carried out in methanol.
  • Anti solvent is selected from common solvents such as ethyl acetate, acetonitrile, toluene and acetone, but the preferred anti solvent is acetone.
  • US application 2004/0006237 (WO 03/048135) relates to novel amorphous and novel crystalline forms III, IV, V of losartan potassium and the processes for their preparation.
  • the patent also discloses novel processes for preparing losartan potassium forms I and II.
  • the preparation of amorphous losartan includes the step of dissolving losartan potassium in a solvent to form a solution and distilling the solvent form the solution to dryness.
  • Losartan form III (hydrated) is obtained by exposing losartan potassium amorphous or form I to an atmosphere having high relative humidity.
  • Losartan potassium form IV is obtained by treating a saturated solution of losartan potassium in ethanol with methylene chloride.
  • Losartan form V is obtained by treating a saturated solution of losartan potassium in ethanol with hexane.
  • Losartan potassium form II is obtained by adding a saturated solution of losartan potassium in ethanol to xylene to form a mixture and evaporating ethanol from the mixture.
  • Losartan form I is obtained by treating a saturated solution of losartan potassium in ethanol or iso propanol, with less soluble solvent like ethyl acetate, toluene, acetone, methyl ethyl ketone, methylene chloride, acetonitrile, dimethyl carbonate or hexane.
  • US application 2004/0034077 discloses a process for preparing losartan and losartan potassium, wherein trityl losartan is treated with an acid in a diluent comprising a ketone.
  • a diluent comprising a ketone.
  • Especially preferred liquid ketones are acetone, methyl ethyl ketone and methyl isobutyl ketone, and acetone being the most preferred.
  • Acids which have been found suitable, include hydrochloric acid, sulphuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid and formic acid.
  • Preferred bases are alkali metal hydroxides and alkoxides. After addition of the base, the liquid ketone is evaporated under vacuum. After separation of triaryl methyl alcohol the residue is acidified to yield losartan. Free losartan is suspended in an alcohol and treated with a solution of potassium ions. Finally losartan potassium is precipitated from the alcohol.
  • the alcohol is selected from the group consisting of isopropyl alcohol, butyl alcohol and isobutyl alcohol.
  • the potassium ion solution is prepared by dissolving potassium iso propoxide, potassium butoxide and potassium iso butoxide or potassium hydroxide in the diluent.
  • US application 2004/0097568 discloses a process for preparing form III of losartan potassium, wherein trityl losartan is treated with aqueous solution of potassium hydroxide in methanol to obtain losartan potassium.
  • the solvent is evaporated under vacuum and traces of water are removed as an azeotrope with toluene.
  • Methanol and carbon are added to the resulting mixture.
  • the carbon is filtered and the methanol is distilled.
  • the resulting mixture is cooled to 20-25°C to obtain crystalline form III losartan potassium.
  • the present invention relates to the disclosure of an efficient and cost effective method of synthesis of losartan potassium comprising the preparation of trityl losartan by reacting N- triphenylmethyI-5- [4'-(bromomethyl) biphenyl-2-yl] tetrazole [IV] and 2-n-butyl 4-chloro 1H- imidazol 5-ca ⁇ boxaldehyde [VI] in a biphasic solvent system comprising water and an organic solvent under phase transfer catalysis in alkaline conditions, followed by in situ reduction using sodium borohydride.
  • the trityl losartan thus obtained is suspended in an alcoholic solvent and heated to temperature of about 35 to reflux temperature of the solvent in the absence of acid or base catalysts to deprotect trityl losartan.
  • the solvent is distilled off under reduced pressure to leave a residue that is then taken up in an organic solvent.
  • the precipitated free losartan is filtered off and free losartan is suspended in an organic solvent capable of forming azeotrope with water and treated with aqueous potassium hydroxide solution.
  • the solution is distilled to remove water as an azeotrope till moisture content of the mixture is less than 0.1 %.
  • losartan potassium crystallizes in polymorphic form-I and is isolated by filtration.
  • the residue obtained after distillation of alcoholic solvent is taken up in an organic solvent and treated with aqueous potassium hydroxide solution to dissolve losartan as its potassium salt.
  • the layers are separated and water is removed from the aqueous solution as an azeotrope with an organic solvent as before.
  • the aim of the present invention is to develop an improved process that eliminates the disadvantages of the prior art process for synthesis of Trityl Losartan and also to provide a novel process to prepare polymorphic form I of Losartan potassium.
  • the present invention provides an improved process that eliminates the disadvantages of the prior art processes for synthesis of trityl losartan and also to eliminate extensive purification procedures to separate the regio isomer.
  • the coupling reaction between intermediates (IV) and (VI) is carried out in presence of a base and phase transfer catalyst in an aqueous/organic biphasic solvent system where organic solvent is selected from toluene, xylene, pentane, heptane, octane, cyclohexane etc.
  • organic solvent is selected from toluene, xylene, pentane, heptane, octane, cyclohexane etc.
  • the reaction is carried out in toluene.
  • the reaction temperature varies from 25 °C to reflux temperature of the solvent, preferably from 80 to 100°C.
  • the phase transfer catalyst is selected from any of the tetra alkyl ammonium halides or tetra alkyl phosphonium halides.
  • the preferred catalyst is tetra butyl ammonium bromide because of its easy availability and low cost.
  • the quantity of the catalyst used varies from about 0.1 to 5mol% with about 2moI% being most suitable.
  • the base employed is selected from alkali metal hydroxides such as lithium hydroxide; sodium hydroxide or potassium hydroxide the preferred base is potassium hydroxide in about 100mol% to 300mol% with about 130mol% being most suitable.
  • the reaction is carried out from ambient temperature to reflux temperature of the solvent and it generally takes 2-10 hours to go to completion.
  • the reaction is conducted at 80-90°C for about 3-4 hours.
  • the reaction mixture is diluted with water and allowed to settle.
  • the aqueous phase is removed and the organic phase is washed with water to remove any traces of phase transfer catalyst and base.
  • the organic phase is then diluted with an alcohol selected from any of C1-C4 alcohols, preferably methanol and reduced with sodium borohydride in quantities ranging from 0.2 equivalents to 2 equivalents.
  • abou t 0.5 equivalent of sodium borohydride is' used.
  • the reduction is carried out in a temperature range of about -10 to +20°C with 0-5°C being most appropriate.
  • the alcohol acts as a protonating source during the reduction of the aldehyde VII to trityl losartan.
  • the reaction When the reaction has proceeded to a desired stage, it is quenched by addition of water.
  • the desired product precipitates from the reaction mass. It is then isolated by filtration.
  • the product thus isolated is about 96% pure and can be utilized for the production of Losartan potassium directly without any further purification. Thus in a "one pot" operation, synthesis of trityl losartan is achieved.
  • the present invention also provides novel methods for preparing losartan potassium form-I.
  • the detritylation is generally carried out in presence of an acid or a base.
  • the cleavage of the trityl group is achieved with strong acid such as hydrochloric acid or sulphuric acid and the desired losartan potassium is isolated after extensive work up.
  • trityl losartan is treated with potassium hydroxide in methanol to obtain losartan potassium in situ.
  • losartan can be easily obtained by heating trityl losartan in an alcoholic solvent, in the absence of an acid or a base catalyst.
  • the alcoholic solvent is selected from any C1 -C4 alcohols.
  • the preferred solvent is methanol.
  • the reaction is carried out at ambient temperature to reflux temperature of the solvent and it generally takes 2-12 hour for completion. Typically the reaction is conducted at reflux temperature for 4-5 hour. After completion of the reaction, alcoholic solvent is distilled off under reduced pressure. The resulting mass containing trityl methyl ether (by product) and free losartan is suspended in an organic solvent (A).
  • the organic solvent (A) is selected from the group consisting of toluene, ethyl acetate, acetone, acetonitrile and methylene chloride.
  • the preferred solvent is toluene.
  • the trityl methyl ether being freely soluble in toluene is extracted into solvent where as the free losartan remains insoluble.
  • the resulting suspension is filtered and washed with toluene to obtain free losartan.
  • the free losartan obtained is suspended in another organic solvent (B) that is capable of forming an azeotrope with water and treated with aqueous potassium hydroxide solution to obtain a clear solution.
  • the quantity of base used varies from about 0.98 - 1 equivalent with respect to the starting material, with 1 equivalent being most suitable.
  • the solution is distilled to remove water as an azeotrope till moisture content of the mixture is less than 0.1 %.
  • losartan potassium crystallizes in polymorphic form-I and is isolated by filtration.
  • a suspension of trityl losartan in methanol is refluxed for about 4-5h.
  • the solid slowly dissolves and deprotection takes place.
  • methanol is distilled off under reduced pressure.
  • the resulting mass is taken up in toluene in which trityl methyl ether is freely soluble.
  • the free losartan remains insoluble and is filtered.
  • the free losartan thus obtained is suspended in a solvent capable of forming an azeotrope with water and treated with concentrated solution of aqueous potassium hydroxide. The mixture is stirred to obtain a clear solution.
  • the solvents can be selected from acetonitrile, acetone, 2-butanone, ethyl acetate and toluene.
  • the preferred solvent is acetoniti ile
  • the solution is distilled to remove water as an azeotrope (boiling point 76.5 C C).
  • the d istillation is continued till the moisture content of the solution is less than 0 1 %.
  • the mass is cooled to room temperature and crystalline solid thus obtained is filtered and found to be form I as established by extensive analytical methods.
  • the free losartan is suspended in acetonitrile and treated with concentrated solution of aqueous potassium hydroxide. The mixture is stirred to obtain a clear solu tion. The solution is diluted with isopropyl ether and the resulting solution is distilled to remove water as ternary azeotrope (59°C). The ternary azeotrope has a lower boiling point than the binary azeotrope. The distillation is continued till the moisture content of the solution is less than 0.1 % . The crystalline solid thus obtained is filtered and found to be form I as established by extensive analytical methods.
  • a suspension of trityl losartan in methanol is refluxed for about 4-5 hours.
  • methanol is distilled off under reduced pressure.
  • the resulting mass is suspended in toluene and treated with aqueous potassium hydroxide solution.
  • the mixture is stirred to obtain a clear solution.
  • the aqueous layer containing losartan potassium is separated.
  • Fresh toluene is added and water is removed as an azeotrope with toluene (85°C). The distillation is continued till the moisture content of the solution is less than 0.1%.
  • the crystalline solid thus obtained is filtered and found to be form I.
  • trityl losartan is treated with ethanolic potassium hydroxide solution.
  • the mixture is diluted with water to precipitate trityl methyl ether.
  • the precipitated trityl methyl ether is filtered.
  • Resulting solution is further diluted with 2-butanone.
  • the solution is distilled to remove water as a ternary azeotrope (73.2°C). When the solution is dry the potassium salt crystallizes.
  • the crystalline solid thus obtained is filtered and found to be form I as established by extensive analytical methods.
  • Example-2 Preparation of trityl losartan: To 50 ml of xylene, N- (triphenylmethyl)-5-[4'-(bromomethyl) biphenyl-2-yI] tetrazole [9.0 g; 0.0164 mol], 2-n-butyl 4-chloro 1 H-imidazol 5-carboxaldehyde [2.83 g; 0.015mol], tetra butyl ammonium bromide [0.217 g; 0.0006 moll and a solution of potassium hydroxide (1.21 g in 15 ml of water) are added. The reaction is vigorously stirred and refluxed for 3.5 hours. The progress of the reaction is monitored by HPLC. The reaction mass is cooled to room temperature and is allowed to settle The lower aqueous layei is discai ded and the xylene layer is washed with water
  • N- (triphenyImethyl)-5-[4'-(bromomethyl) biphenyl-2-yl] tetrazole [9.0 g; 0.0164 mol]
  • 2-n-butyl 4-chloro I H-imidazol 5-carboxaldehyde [2.83 g; 0.015mol]
  • cetrimide [0.03 g; 0.00035 mol]
  • a solution of potassium hydroxide (1.29 g in 15 ml of water)
  • N- (triphenylmethyl)-5-[4'-(bromomethyI) biphenyl-2-yl] tetrazole [10.2 g; 0.018 mol]
  • 2-n-butyl 4-chloro IH-imidazol 5-carboxaldehyde [3.4 g; 0.018 mol]
  • tetra butyl ammonium bromide [0.2618 g; 0.00081 mol]
  • a solution of potassium hydroxide (1.45 g in 15 ml of water)
  • Trityl losartan (50g; 0.075mol) is suspended in methanol (250ml). The resulting mixture is refluxed for 4-5 hours to obtain a clear solution Methanol is distilled off under reduced pressure.
  • Trityl losartan (200g; 0.3mol) is suspended in methanol (1 L). The resulting mixture is refluxed for 4-5 hours to obtain a clear solulion. Methanol is distilled off under reduced pressure. The resulting mass is suspended in toluene (1 L) and treated with a solution of potassium hydroxide (85%, 20g; 0 3 mol) in water (500ml). The mixture is stirred for 15-20 min. to obtain a clear solution. The aqueous layer containing losartan potassium is separated. Fresh toluene (1.2L) is added to the aqueous solution. The resulting mixture is distilled to remove water as an azeotrope. The distillation is continued till the moisture content of the solution is less than 0.1 %. The crystalline solid thus obtained is filtered and found to be form I as established by extensive analytical methods. Yield: 125g (92%)
  • Prep ⁇ r ⁇ tion oflos ⁇ rt ⁇ n potassium form 1 A suspension of free losartan (25g; 0.059mol) in acetonitrile (150ml) is treated with a solution of potassium hydroxide (85%, 3.9g; 0.059 mol) in water (20ml). The mixture is stirred for 15-20 min. to obtain a clear solution. T he solution is diluted with isopropyl ether (150ml). The resulting solution is distilled to remove water as an azeotrope. The distillation is continued till the moisture content of the solution is less than 0.1 % . The crystalline solid thus obtained is filtered and found to be form I as established by extensive analytical methods. Yield: 25g (92%) Example-10
  • a suspension of free losaitan (25g 0059mol) in acetonittile (500ml) is treated with a solution of potassium hydioxide (85%, 39g, 0059 mol) in watei (J5ml)
  • the mixture is stirred for 15-20 min to obtain a clear solution
  • the lesulting solution is distilled to remove water as an azeotrope
  • the distillation is continued with drop wise addition of acetonitrile (500ml), till the moisture content of the solution is less than 01%
  • the ciystalline solid thus obtained is filtered and found to be form I as established by extensive analytical methods Yield 25g(92%)

Abstract

Méthode nouvelle de préparation de trityl Losartan et de Losartan potassium de forme I.
PCT/IB2004/002879 2003-09-04 2004-09-04 Methode de preparation de losartan potassium de forme i WO2005023758A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP04769282A EP1663998A2 (fr) 2003-09-04 2004-09-04 Methode de preparation de losartan potassium de forme i
US10/570,824 US20070249839A1 (en) 2003-09-04 2006-10-31 Process for the Preparation of Losartan Potassium Form I

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN907MU2003 2003-09-04
IN907/MUM/2003 2003-09-04

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WO2005023758A3 WO2005023758A3 (fr) 2006-03-23

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006038223A1 (fr) * 2004-10-06 2006-04-13 Matrix Laboratories Ltd Procede de preparation du 2-n-butyl-4-chloro-1-{[2’-(2-triphenylmethyl-2h-tetrazole-5-yl)-1,1’-biphenyl-4-yl]methyl}-ih-imidazole-5-methanol (intermediaire du losartan)
WO2007119246A2 (fr) * 2006-04-17 2007-10-25 Unichem Laboratories Limited Procédé amélioré destiné à la production de potassium de losartan
JP2013505961A (ja) * 2009-09-29 2013-02-21 セラヴァンス， インコーポレーテッド ビフェニルイミダゾール化合物の調製方法
CN108047208A (zh) * 2018-01-12 2018-05-18 浙江华海药业股份有限公司 一种降低氯沙坦二聚物杂质的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5310928A (en) * 1991-11-18 1994-05-10 E. I. Du Pont De Nemours And Company Process for preparing biphenyltetrazole compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5310928A (en) * 1991-11-18 1994-05-10 E. I. Du Pont De Nemours And Company Process for preparing biphenyltetrazole compounds

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006038223A1 (fr) * 2004-10-06 2006-04-13 Matrix Laboratories Ltd Procede de preparation du 2-n-butyl-4-chloro-1-{[2’-(2-triphenylmethyl-2h-tetrazole-5-yl)-1,1’-biphenyl-4-yl]methyl}-ih-imidazole-5-methanol (intermediaire du losartan)
WO2007119246A2 (fr) * 2006-04-17 2007-10-25 Unichem Laboratories Limited Procédé amélioré destiné à la production de potassium de losartan
WO2007119246A3 (fr) * 2006-04-17 2009-04-30 Unichem Lab Ltd Procédé amélioré destiné à la production de potassium de losartan
JP2013505961A (ja) * 2009-09-29 2013-02-21 セラヴァンス， インコーポレーテッド ビフェニルイミダゾール化合物の調製方法
US9221763B2 (en) 2009-09-29 2015-12-29 Theravance Biopharma R&D Ip, Llc Process for preparing biphenyl imidazole compounds
CN108047208A (zh) * 2018-01-12 2018-05-18 浙江华海药业股份有限公司 一种降低氯沙坦二聚物杂质的方法
CN108047208B (zh) * 2018-01-12 2022-03-22 浙江华海药业股份有限公司 一种降低氯沙坦二聚物杂质的方法

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EP1663998A2 (fr) 2006-06-07
US20070249839A1 (en) 2007-10-25

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